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Right on

For decades, scientists have been mistaken in their assumptions about two childhood brain tumors. Thanks to St. Jude research, they’re now on the right track.

Your mother stands corrected. Sometimes two wrongs do, in fact, make a right.

Once upon a time—not long ago—scientists regarded medulloblastoma as a single disease. They were also confident that this malignant brain tumor always originated in cells located in the cerebellum.

The scientific community was wrong on both counts.

Developmental neurobiologist Richard Gilbertson, MD, PhD, of St. Jude Children’s Research Hospital led research teams that disproved these well-known “facts.” For the past several years, he and his team have been trying to figure out why one child would be cured of brain cancer while another would not. Why did these children have such variable responses to therapy?

“Back in 2005, we used genomic technologies to show that medulloblastoma is not one disease,” he explains. “We started to carve this apparently single disease into subgroups that shared similar genetics and similar clinical behaviors.”

Researchers have used this same technique for a number of adult diseases such as lung cancer and liver cancer.

“But the obvious elephant-in-the-room question was, ‘Where do those subgroups come from?’” Gilbertson says. “If there are different subgroups, how do we get them? Is this all one disease that comes from the same place and ends up being different? Or are these different diseases, but we just call them the same thing because they arise in a similar part of the body and look alike under the microscope?’”

Asking the right questions

A couple of years ago, an international team led by Gilbertson began asking those questions about ependymoma, the third most common brain tumor in children. The researchers suspected that the cancer known as ependymoma was actually several diseases that were intrinsically different from the start.

Gathering 204 ependymoma samples from patients in the U.S., Europe and Canada, the team conducted the world’s most comprehensive analysis of the ependymoma genome. As part of that study, scientists developed a method for tracing the molecular origins of different cancers, expanding the number of ependymoma subtypes to nine and identifying more than 200 genes that may cause the tumor to develop or spread. Scientists identified EPHB2 as the first gene proven to cause ependymoma. The team also created the first laboratory model for the disease and pinpointed the stem cells responsible for specific subytpes. In July of 2010, the researchers published their findings in the journal Nature.

As a result of that study, Gilbertson and his team collaborated with Kip Guy, PhD, St. Jude chair of Chemical Biology and Therapeutics, to screen thousands of drugs to find a compound that would be effective against ependymoma. Scientists used the model created in Gilbertson’s lab to test the compound. The scientists were surprised to discover that a drug that has long been used to treat colorectal and breast cancer was also effective against ependymoma.

“There are about 300 FDA-approved compounds out there for cancer,” Gilbertson says. “If you wanted to test those in kids with ependymoma, it would take years. But our new model enabled us to screen all of those drugs to see if any of them had value. We discovered that this drug is highly potent for kids with ependymoma. We would never have known that if not for the new model.”

Clinicians are already using the compound in the clinic and expect to incorporate it into the next St. Jude clinical trial for ependymoma.

Growing up

Flush with success, Gilbertson and his colleagues applied similar techniques to medulloblastoma, the most common brain tumor in children. The investigators concentrated their efforts on the wingless (WNT) and sonic hedgehog subtypes of medulloblastoma. These subgroups derive their peculiar names from the biochemical pathways that are activated in the resulting tumors. Together, the two subtypes account for about 40 percent of medulloblastoma tumors.

First, scientists used gene expression mapping to determine where the hedgehog genes were expressed. Not surprisingly, they were expressed in the cerebellum. But scientists were shocked to discover that the WNT genes were expressed far from the cerebellum—on a distant, lower part of the brainstem. Cells in that area had never before been linked to cancer.

“When you scan kids with medulloblastoma, they always have tumors in the cerebellum, which is why everyone thought the cancer started there,” Gilbertson says. But St. Jude scientists noted that there were many children whose tumors also attached to the brainstem.

“We thought those tumors started in the cerebellum and grew down into the brainstem,” says postdoctoral fellow Paul Gibson, PhD, first author of a paper on this research that appeared in a recent issue of Nature. “We now know that the WNT subtype begins in the brainstem and grows up into the cerebellum. It completely changes the way that people think about medulloblastoma and opens up a new way of thinking about treatment.”

The right track

Children with WNT tumors fare extremely well. “We’ve cured almost every kid at St. Jude with that disease,” Gilbertson says.

In contrast, WNT’s dangerous cousin, sonic hedgehog, tends to attack extremely young children and has a lower survival rate. Now that scientists can differentiate between the two subtypes, they hope to tailor treatment accordingly. In the past, all children with medulloblastoma have received cranial irradiation, which can result in cognitive deficits. Older children with the disease may also encounter fertility problems when they become adults. Scientists aim to develop novel, less-toxic treatments for children with the WNT subtype so that they avoid such harsh side effects.

The medulloblastoma findings may transform the diagnosis and treatment of the disease. In fact, children in the hospital’s upcoming medulloblastoma clinical trial will benefit from this research.

“We are pretty confident that we can pick out the good actors and the bad actors,” Gilbertson says, “so our next step will take this work and apply it to clinical practice.” That protocol is slated to open in the summer of 2011.

These latest discoveries bring Gilbertson one step closer to fulfilling his personal aspirations.

“My ambition when I was at medical school was to cure at least two of the top brain tumors in kids—that remains my goal,” he says. “It’s not an unrealistic pipe dream. We have great science and a great clinic right at each other’s doorstep, and they interact beautifully. I could not do this science anywhere else in the world. Thanks to the terrific and unique environment at St. Jude, I’m beginning to believe that we will someday do it.”